The increasing resistance of bacterial pathogens to antibiotics, combined with fundamental advances in understanding the mechanisms and regulation of bacterial virulence, has prompted the identification of pathogen anti-virulence drugs that antagonize the activity of virulence factors. Cholera is an acute intestinal infection caused by the bacterium Vibrio cholerae, a gram-negative flagellated bacillus. In addition to being a class B bioterrorism threat, cholera is more widespread today than it was in the previous century. The expression of V. cholerae's primary virulence factors, the toxin-coregulated pilus (TCP) and cholera toxin (CT), occurs via a transcriptional cascade involving several activator proteins, and serves as a paradigm for the regulation of bacterial virulence. Strains of V. cholerae capable of causing the significant epidemics and pandemics of cholera that have occurred throughout history possess two genetic elements, the Vibrio pathogenicity island (VPI) and the lysogenic CTX phage. Both of these elements have inserted into the circular chromosome I and are present in the pathogenic forms of the organism. The VPI contains the genes responsible for the synthesis and assembly of the essential colonization factor TCP, and the CTX phage encodes the CT genes. Expression of the TCP and CT genes is coordinately regulated at the transcriptional level by a virulence cascade involving activator proteins encoded both within the VPI and the ancestral genome. AphA and AphB initiate the expression of the cascade by a novel interaction at the tcpPH promoter. AphA is a member of a new regulator family and AphB is a LysR-type activator, one of the largest transcriptional regulatory families. Once expressed, cooperation between TcpP/TcpH and the homologous transmembrane activators ToxR/ToxS activates the toxT promoter. ToxT, an AraC/XylS (A/X) type regulator, then directly activates the promoters of the primary virulence factors. Thus, ToxT is the paramount regulator of virulence gene expression.
ToxT inhibitors have been identified and shown to provide protection against intestinal colonization by V. cholerae. For example, bile (Schuhmacher, et al. (1999) J. Bacteriol. 181:1508-14) and several of its unsaturated fatty acid constituents, i.e., oleic acid, linoleic acid, and arachidonic acid (Chatterjee, et al. (2007) Infect. Immun. 75:1946-53) have been shown to inhibit virulence factor gene expression. Similarly, virstatin, a small molecule 4-[N-(1,8-naphthalimide)]-n-butyric acid, has been shown to inhibit virulence regulation in V. cholerae (Hung, et al. (2005) Science 310(5748):670-4). Further, U.S. Pat. No. 5,866,150 teaches compounds having the structure: CH3(CH2)n—CH═CH—CH2CH═CH—(CH2)n—R—COOR′ for use in treating bacterial infections including, e.g., S. aureus, V. cholera, S. dysenteria, B. substilis, and S. typhemurium. 
High resolution structure of ToxT has shown that ToxT contains an almost completely buried and solvent inaccessible sixteen carbon fatty acid bound to a pocket in the N-terminal domain, which can influence its DNA binding activity. In particular, virulence gene expression can be reduced between 6-8 fold with cis-palmitoleic acid and 10-15 fold with oleic acid (Lowden, et al. (2010) Proc. Natl. Acad. Sci. USA 107:2860-5).